The invention generally relates to phospholipids ether analogs and use thereof and specifically relates to use of phospholipid ether analogs and combinations thereof for diagnosis of metastasis, treatment, pharmacokinetic, dosimetry, and toxicity studies of various cancer types, such as non-small cell lung cancer, prostate cancer and metastasis thereof.
Non-small Cell Lung Cancer (NSCLC)
Non-small cell lung cancer (NSCLC) is the leading cause of cancer death in the United States today. Surgical resection in appropriately selected patients offers the best chance for cure. Accurate pre-operative assessment of local, regional and distant metastatic spread is thus critical for optimal management.
Imaging with FDG PET scanning has recently become the “gold standard” for imaging NSCLC, due to improved sensitivity, particularly when compared with CT imaging. However, its sensitivity for identifying mediastinal lymph node involvement is only about 90%, and lack of specificity, particularly in patients with inflammatory or granulomatous disease, is particularly problematic. Furthermore, its utility in diagnosing brain tumors or metastases is limited due to high metabolic background of normal brain tissue.
Evaluation of the mediastinal lymph node status is essential because nodal metastasis, which occurs in nearly half of all patients with NSCLC, is probably the most frequent barrier to cure. Accurate staging may also spare patients the morbidity of unnecessary, non-curative surgical procedures. Hence, there remains a need for an imaging technique that is more sensitive, specific, and accurate than any currently available technology.
Current conventional modalities have limitations. Anatomic imaging with computed tomography (CT) and magnetic resonance imaging (MRI) are impractical for whole body screening but are the most widely used non-invasive imaging methods for evaluation of loco-regional spread. However, CT relies on size criteria of over one centimeter for diagnosing abnormal nodes.
Positron-emission tomography (PET) scanning with 18F-fluorodeoxyglucose (FDG) has generated considerable interest as an oncologic imaging technique. A recent study prospectively compared the ability of a standard approach to staging for NSCLC (CT, ultrasound, bone scanning, etc) and PET scanning to detect metastases in mediastinal lymph nodes and distant sites. Mediastinal involvement was confirmed histopathologically, and distant metastases were confirmed by other imaging tests. The sensitivity and specificity of PET for detecting mediastinal metastases were 91% and 86%, respectively; for detecting distant metastases, 82% and 93%, respectively. This compares to sensitivity and specificity for CT scanning of mediastinal involvement 75% and 66%, respectively. A meta-analysis involving 39 studies and over 1000 patients also found that FDG-PET was more accurate than CT for mediastinal staging, (sensitivity and specificity of 85% and 90%, respectively, for FDG-PET and 61% and 79% for CT scanning), although FDG-PET became less specific when CT showed enlarged mediastinal lymph nodes (78%).
FDG-PET has been shown to reduce futile thoracotomies in patients. However, because of the false positive and false negative rate, confirmatory mediastinoscopies are often recommended. For example, a retrospective study involving over 200 patients with NSCLC found that the sensitivity, specificity, positive and negative predictive values, and accuracy for FDG-PET were 64%, 77%, 45%, 88%, and 75%, respectively.
FDG-PET also plays a role in diagnosing extra-thoracic disease, particularly in patients with intermediate stages of lung cancer. A study done by the American College of Physicians involving over 300 patients found that unsuspected metastatic disease or second primary malignancies was identified in 18 of 287 patients (6.3%). Some studies, although not all, suggest that by correctly identifying advanced disease, PET will avoid unnecessary thoracotomy on 1 in 5 patients.
Conventional anatomic imaging techniques such as CT scanning are also poor at predicting survival following treatment. In a recent study involving 73 NSCLC patients receiving treatment with concurrent cisplatin-based chemo/radiotherapy or radiotherapy alone for advanced disease, response by conventional CT imaging did not correlate with survival. Response by FDG-PET scans, however, did correlate strongly with survival (p<0.001). Survival from the date of a follow-up PET scan was 84% and 84% at 1 and 2 years respectively for 24 patients who had achieved a complete response on PET, but only 43% and 31% of the 32 patients who did not (p=0.010). These results corroborate similar findings reported recently by other authors, which also show a correlation of uptake on PET scan with biological aggressiveness of tumor, and that PET imaging late after completion of treatment is highly predictive of future survival.
It is generally accepted that FDG-PET imaging is a poor method of identifying metastatic disease to the brain in patients with NSCLC. Under normal conditions, the gray matter of the brain has high glucose utilization and therefore the uptake of FDG is normally high. While cerebral metastatic disease is often quite metabolic and often does demonstrate increased FDG uptake, it frequently is less than the brain gray matter and therefore the cerebral metastases may not be conspicuous. In one series, the sensitivity and specificity for the identification of cerebral metastatic disease in patients with NSCLC was 60% and 99% for FDG-PET, and 100% and 100% for conventional imaging. Therefore, FDG-PET imaging is not considered to be the best method of evaluating a patient with NSCLC for metastatic disease to the brain.
Another disadvantage of FDG is that it is not specific for tumors, but accumulates in both malignant and non-malignant hypermetabolic tissues. The overwhelming majority of false positive results (positive result when the radiological abnormality is not due to cancer) with FDG-PET scans of the lung are due to inflammatory and infectious causes. FDG is a nonspecific tracer and accumulates in areas of infection or inflammation. In the lung, these areas can be localized lung parenchymal nodules or more diffuse (subsegmental, segmental or lobar) or in the hilar and mediastinal nodes. In a recent study from Japan, of 116 lung nodules 1-3 cm in diameter, 15 out of 73 malignant nodules were false negative on FDG-PET and 15 out of 43 benign nodules were false positive on FDG-PET. In focal pneumonias causing ground glass opacity nodules, the false positive rate was as high as 80%. In another study, ten patients with extrapulmonary cancer had false positive FDG-PET uptake in the lung; 6 had intense focal or multifocal uptake and four had uptake in a more segmental or lobar pattern. In all 10 patients, the uptake was due to consolidation or atelectasis and the final diagnosis on follow-up was pulmonary inflammation or infection. In addition to active bacterial pneumonias, false positive FDG-PET results can occur in many other infectious and inflammatory conditions in the lung. In the Midwestern US, many asymptomatic people have lung nodules and enlarged nodes due to previous infection with histoplasma; although many of these nodules are quiescent, some represent smoldering or active infection. Pulmonary sarcoidosis is probably one of the more common active inflammatory granulomatous processes in the lung. Interestingly, when serial FDG-PET scans have been performed in a patient being treated with oral corticosteroids for pulmonary sarcoidosis, FDG uptake decreased and then vanished.
FDG-PET is also frequently negative in malignancies with a low metabolic rate, such as bronchoalveolar carcinoma or carcinoid.
Therefore a radiopharmaceutical that could accurately identify early metastatic disease in the patients with NSCLC would have a significant impact on patient care, in terms of both staging and response to therapy. Although PET imaging has improved diagnostic efficacy in this area compared to CT, there remains a need for an accurate imaging technique that is not based upon metabolic activity, which is non-specific, but is based upon a tumor-specific function that can non-invasively screen the whole body, including the brain.
Prostate Cancer
Approximately 230,110 new cases of prostate cancer will be diagnosed in the United States for the year 2004 alone. Despite technical refinements in definitive local treatment of clinically organ confined prostate cancer by radical prostatectomy, such that many men are cured with primary therapy alone, as many as 40% of patients will experience biochemical recurrence with long-term follow-up. This recurrence is typically defined as a post-operative PSA level which is greater than or equal to 0.4 ng/ml since patients with PSA levels above this threshold generally develop clinical evidence for recurrence within 6-49 months although a PSA level of greater than or equal to 0.2 has been proposed more recently. With limited success, clinical and pathologic criteria are currently utilized to determine the likelihood for systemic disease recurrence. Factors increasing the likelihood of systemic recurrence include a high preoperative PSA level as well as pathologic features of the surgical specimen including Gleason score>7, seminal vesicle involvement, and lymph node involvement. In contrast, extracapsular extension, positive surgical margins and Gleason score<7 are factors generally associated with local recurrence. In addition, the velocity of PSA rise following prostatectomy has been utilized to determine whether disease recurrence is local or systemic. For instance, Partin et al reported that a PSA rise of less than 0.75 ng/ml/year was more frequently associated with local recurrence. Furthermore, Patel et al reported that a PSA doubling time of greater than 12 months correlated with local recurrence. Despite these clinical and pathologic criteria, the inventors are still unable to accurately select patients appropriately for local therapy such that many men may receive unnecessary hormonal ablation.
One of the greatest challenges in treating patients with clinically organ confined prostate cancer or patients with biochemical recurrence following definitive treatment of presumed organ-confined disease remains to accurately distinguish localized versus metastatic disease. This diagnostic capability is important to identify patients who may benefit from effective local treatment modalities including surgery, external beam radiation, brachytherapy, and cryotherapy. Because the inventors presently do not have an accurate means of staging, patients with occult metastatic disease may unnecessarily undergo local treatment with associated risks of therapy. Furthermore, patients with a rising PSA due to local recurrence, in whom systemic recurrence cannot be excluded with confidence, may unnecessarily undergo hormonal ablation, which is generally not considered curative and is associated with osteoporosis development, decreased libido, weight gain, menopausal symptoms, and overall malaise, as well as the evolution of hormonally independent prostate cancer.
While conventional imaging studies such as computed tomography (CT) and magnetic resonance imaging (MRI) are useful in assessing soft-tissue metastasis, the vast majority of prostate cancer metastasizes to the bone only. Thus, the utility of CT and MRI scanning in assessing the disease is suboptimal and more sensitive imaging modalities for either locally recurrent or metastatic prostate cancer are necessary. Radioimmunoscintigraphy with Indium-111 capromab pendetide (ProstaScint, Cytogen Corp, Princeton, N.J.) has been utilized in patients following prostatectomy with a rising PSA who have a high clinical suspicion of occult metastatic disease and no clear evidence for metastatic disease in other imaging studies. This scan is based on a radiolabeled murine monoclonal antibody which is specific for PSMA (Prostate-specific membrane antigen), a transmembrane protein which is specifically expressed by both normal and malignant prostate epithelial cells. While ProstaScint radioimmunoscintigraphy has been shown to be promising in diagnosing locally recurrent disease in the prostate bed in patients with rising PSA, clinical results for this scan have been somewhat variable, with sensitivities ranging between 44% and 92% and specificities between 36% and 86%. Furthermore, when subsequent biopsy was utilized as the standard of reference for local recurrence, false-negative ProstaScint studies have been reported in 10% to 20% of cases. In addition, false-positive uptake of ProstaScint has been reported in neurofibromatosis, lymphomas, renal carcinomas, pelvic kidneys, myolipomas, and meningiomas, as well as in the bone marrow of vertebral bodies. Given this data, use of the ProstaScint scan for patients at risk for occult metastases from prostate cancer remains controversial.
In patients with metastatic prostate cancer, positron-emission tomography (PET) imaging has recently been used to measure the metabolic activity of osseous metastases. This technique has proven to be effective in distinguishing active bony metastasis from osteoblast activity which occurs as a result of bone healing following successful treatment of metastatic disease. This question can be assessed better by PET than by either bone scan or CT. Furthermore, changes in PET scan findings can be seen as early as 4 weeks following initiation of systemic treatment in patients with metastatic prostate cancer, whereas in many cases no significant change is seen on conventional bone scan. Therefore imaging utilizing PET technology may be useful in monitoring response to treatment in these patients. PET scanning with 18F-FDG has generated considerable interest as an imaging technique. Recently, it has been shown that FDG-PET can distinguish between active and quiescent bone metastases in patients with prostate cancer. The intensity of FDG uptake is thought to reflect the metabolic and biological activity of these lesions in contrast to the traditional bone scan with technetium-diphosphonate compounds in which nonspecific osteoblast activity may be detected as a false positive signal following treatment. In addition, a false negative reading may be obtained since early metastases, which initially seed into the bone marrow, will not necessarily produce a signal until an osteoblastic response occurs. Therefore, a persistently positive bone scan does not necessarily indicate the presence of residual viable metastases and a negative bone scan result may not reflect accurately the patient's metastatic tumor burden. FDG-PET may therefore prove beneficial in guiding the management of patients with bony metastases and in a retrospective study FDG-PET and helical CT have been shown independently to be more effective than 111In-monoclonal antibody imaging in detecting metastatic disease.
Although the FDG-PET scan is a promising imaging technique in patients with prostate cancer, most prostate cancers are slow growing and therefore do not accumulate FDG, and thus do not image well with that agent. Furthermore, FDG is excreted in the urine and so the accumulation of FDG in the bladder will minimize the probability of detecting local recurrences of prostate cancer. Indeed Morris et al reported difficulty in detection of soft tissue metastases by FDG-PET alone when metastatic sites are obscured by anatomic pathways of tracer excretion. More recently, PET-CT has been found to be more effective than PET alone in identifying metastatic lesions in patients with suspected occult metastases. In a prospective study of patients with various tumor types, the specificity and accuracy with multiple radiologic interpretations were significantly higher for PET-CT.
Accordingly, the need exists for developing a more sensitive and specific imaging exam, molecular imaging agent, such as phospholipids ether compounds (PLE). It would be desirable to have tumor-selective radiopharmaceuticals, with minimal accumulation in the bladder, which could accurately identify early metastatic disease in patients with prostate cancer, would have an important impact on patient care, in terms of both staging and response to therapy.